Inhibition of hERG Potassium Channels by the Polycylic Aromatic Hydrocarbon Phenanthrene

Abstract

Polycyclic aromatic hydrocarbons (PAHs) may contribute to cardiotoxic effects of hydrocarbon-based pollution. Phenanthrene (Phen) is an abundant PAH in polluted air and water. For example, Phen is a constituent PAH of crude oil spills and has been shown to increase ventricular action potential duration of fish ventricular myocytes. This action is associated with inhibition of the rapid delayed rectifier K+-current. Ether-à-go-go Related Gene encoded potassium channels (ERG) mediate IKr in multiple species including fish and human, and block of human ERG (hERG) channels by structurally diverse drugs can result in acquired long QT syndrome in humans. The purpose of this study was to investigate the action of Phen on hERG, using whole-cell patch-clamp recording from HEK 293 cells expressing wild-type (WT) or mutant hERG channels. Under conventional voltage-clamp, WT hERG current (IhERG) tails at −40 mV following an activating protocol were inhibited with an IC50 of 16.8 ± 1.7 µM, Hill slope: 1.0 ± 0.1 (mean ± SEM; n= at least 5 for 5 different concentrations). Phen (10 µM) inhibition of IhERG was voltage-dependent and was associated with leftward shift of voltage-dependent activation (V0.5 shift of −10.1 ± 0.9 mV; n=16). The extent of observed IhERG inhibition also varied with duration of the activating voltage command. IhERG carried by the attenuated inactivation N588K hERG mutant was markedly less sensitive to Phen and the F557L mutation in the S5 domain also reduced Phen inhibition. Thus, the observed IKr block with Phen appears to involve a direct inhibitory effect of the compound on (h)ERG channels that is contingent on channel gating. Intact inactivation gating and availability of the F557 residue appear to be significant influences on this inhibitory action. Funded by the British Heart Foundation PG/17/77/33125